title: The third-generation P-glycoprotein inhibitor tariquidar may overcome bacterial multidrug resistance by increasing intracellular drug concentration.
abstract: OBJECTIVE
  The use of efflux pump inhibitors may be a powerful strategy to overcome transporter-mediated bacterial multidrug resistance. In the present study, we set out to investigate the potency of tariquidar, a third-generation P-glycoprotein inhibitor in clinical development, for overcoming bacterial resistance towards ciprofloxacin.
  
  
  METHODS
  Staphylococcus aureus 29213 (SA29213) and S. aureus 1199B (SA1199B), which overexpresses the multidrug transporter NorA, as well as Pseudomonas aeruginosa 27853 and Stenotrophomonas maltophilia BAA-85, which expresses SmeDEF, were exposed to ciprofloxacin in the presence and absence of tariquidar or, for comparative reasons, elacridar. Activity of both P-glycoprotein inhibitors was evaluated by determination of MICs and time-kill curves, and by quantification of uptake of ciprofloxacin into bacterial cells.
  
  
  RESULTS
  Activity of tariquidar and elacridar was comparable for S. aureus strains, and both dose-dependently increased susceptibility towards ciprofloxacin. Highest effects were observed for SA1199B, where the addition of tariquidar resulted in a 10-fold reduction of the ciprofloxacin MIC, while no effect was observed for P. aeruginosa. For S. maltophilia, elacridar but not tariquidar improved susceptibility. Uptake of [14C]ciprofloxacin and modification of susceptibility showed significant correlations (r=0.89, P<0.0001). Tariquidar had no intrinsic activity against any strain tested.
  
  
  CONCLUSIONS
  We conclude that tariquidar has potent inhibitory effect against certain bacterial efflux pumps in vitro. Their high activity at clinically achievable concentrations might yield this class of drugs promising for future applications in infectious diseases.
authors.affiliation: Department of Clinical Pharmacology, Medical University Vienna, Vienna, Austria.
authors.forename: I
authors.initials: I
authors.lastname: Leitner
authors.forename: J
authors.initials: J
authors.lastname: Nemeth
authors.forename: T
authors.initials: T
authors.lastname: Feurstein
authors.forename: A
authors.initials: A
authors.lastname: Abrahim
authors.forename: P
authors.initials: P
authors.lastname: Matzneller
authors.forename: H
authors.initials: H
authors.lastname: Lagler
authors.forename: T
authors.initials: T
authors.lastname: Erker
authors.forename: O
authors.initials: O
authors.lastname: Langer
authors.forename: M
authors.initials: M
authors.lastname: Zeitlinger
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D011804:Quinolines / Q000378:metabolism* / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects; D020615:Stenotrophomonas maltophilia / Q000187:drug effects; D013997:Time Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D011804:Quinolines; C402343:tariquidar